AR035626A1 - INHIBITORS OF INHIBITORS OF THYROSINE KINASE, PHARMACEUTICAL COMPOSITION, PROCEDURE TO PREPARE IT, AND, USE OF THE COMPOUNDS IN THE PREPARATION OF MEDICINES - Google Patents

INHIBITORS OF INHIBITORS OF THYROSINE KINASE, PHARMACEUTICAL COMPOSITION, PROCEDURE TO PREPARE IT, AND, USE OF THE COMPOUNDS IN THE PREPARATION OF MEDICINES

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AR035626A1
AR035626A1 ARP000105472A ARP000105472A AR035626A1 AR 035626 A1 AR035626 A1 AR 035626A1 AR P000105472 A ARP000105472 A AR P000105472A AR P000105472 A ARP000105472 A AR P000105472A AR 035626 A1 AR035626 A1 AR 035626A1
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Argentina
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alkyl
aob
aryl
cycloalkyl
heterocyclyl
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ARP000105472A
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Spanish (es)
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Merck & Co Inc
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    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract

Se refieren compuestos de indol de fórmula (1) que inhiben, regulan y/o modulan la transducción de senales de tirosina quinasa, las composiciones que contienen estos compuestos, y los métodos de uso de los mismos para tratar enfermedades y condiciones que dependen de tirosina quinasa, tales como angiogénesis, cáncer, desarrollo de tumores, arteriosclerosis, degeneración macular relacionada con la edad, retinopatía diabética, enfermedades inflamatorias, y similares en mamíferos. Reivindicación 1: Un compuesto de indol caracterizado porque es de fórmula (1) o una sal farmacéuticamente aceptable o un estereoisómero del mismo, donde Z es fórmulas (2) o (3) o (4); W1 es S, O o N-R; V1 es N o C; W2 es N o C; V2 es S, O o N-R; a es 0 o 1; b es 0 o 1; m es 0, 1 o 2; s es 1 o 2; t es 1, 2 o 3; X=Y es C=N, N=C, o C=C; R es H o alquilo C1-6; R1 y R5 están independientemente seleccionados de: H, (C=O)aOb alquilo C1-10, (C=O)aOb arilo, (C=O)aOb alquenilo C2-10, (C=O)aOb alquinilo C2-10, CO2H, halo, OH, Ob perfluoroalquilo C1-6, (C=O)a NR7R8, CN, (C=O)aOb cicloalquilo C3-8, y (C=O)aOb heterociclilo, dicho alquilo, arilo, alquenilo, alquinilo cicloalquilo y heterociclilo está opcionalmente sustituido con uno o más sustituyentes seleccionados de R6; R2 y R3 están independientemente seleccionados de: H, (C=O)Oa alquilo C1-6, (C=O)Oa arilo, alquilo C1-6, SO2Ra, y arilo; R4 está seleccionado de: (C=O)aOb alquilo C1-10, (C=O)aOb arilo, (C=O)aOb alquenilo C2-10, (C=O)aOb alquinilo C2-10, CO2H, halo, OH, Ob perfluoralquilo C1-6, (C=O)a NR7R8, CN, (C=O)aOb cicloalquilo C3-8, y (C=O)aOb heterociclilo, dicho alquilo, arilo, alquenilo, alquinilo, cicloalquilo y heterociclilo está opcionalmente sustituido con uno o más sustituyentes seleccionados de R6; R6 es(C=O)aOb alquilo C1-6, (C=O)aOb arilo, alquenilo C2-10, alquinilo C2-10, (C=O)aOb heterociclilo, CO2H, halo, CN, OH, Ob perfluoralquilo C1-3, Oa(C=O)b NR7R8, oxo, CHO, (N=O)R7R8, o (C=O)aOb cicloalquilo C3-8, dicho alquilo, arilo, alquenilo, alquinilo, heterociclilo y cicloalquilo está opcionalmente sustituido con uno o más sustituyentes seleccionados de R6a; R6a está seleccionado de: C=O)rOs alquilo C1-10, donde r y s son independientemente 0 o 1, Or perfluoralquilo C1-3, donde r es 0 o 1, alquileno C0-6-S(O)mRa, donde m es 0, 1 o 2, oxo, OH, halo, CN, alquenilo C2-10, alquinilo C2-10, cicloalquilo C3-6, alquileno C0-6-arilo, alquileno C0-6-heterociclilo, alquileno C0-6-N(Rb)2, C(O)Ra, alquileno C0-6-CO2Ra, C(O)H, y alquileno C0-6-CO2H, dicho alquilo, alquenilo, alquinilo, cicloalquilo, arilo y heterociclilo está opcionalmente sustituido con hasta tres sustituyentes seleccionados de Rb, OH, alcoxi C1-6, halógeno, CO2H, CN, O(C=O) alquilo C1-6, oxo, y N(Rb)2; R7 y R8 están independientemente seleccionados de: H, (C=O)Ob alquilo C1-10, (C=O)Ob cicloalquilo C3-8, (C=O)Ob arilo, (C=O)Ob heterociclilo, alquilo C1-10, arilo, alquenilo C2-10, alquinilo C2-10, heterociclilo, cicloalquilo C3-8, SO2Ra, y (C=O)NRb 2, dicho alquilo, cicloalquilo, arilo, heterociclilo, alquenilo y alquinilo están opcionalmente sustituidos con uno o más sustituyentes seleccionados de R6a, o R7 y R8 pueden estar tomados conjuntamente al nitrógeno al cual están unidos para formar un heterociclo monocíclico o bicíclico con 5-7 miembros en cada anillo y que contiene opcionalmente además del nitrógeno uno o dos heteroátomos adicionales seleccionados de N, O y S, estando dicho heterociclo monocíclico o bicíclico opcionalmente sustituido con uno o más sustituyentes seleccionados de R6a; Ra es alquilo C1-6, cicloalquilo C3-6, arilo, o heterociclilo; y Rb es H, alquilo C1-6, arilo, heterociclilo, cicloalquilo C3-6, (C=O)O alquilo c1-6, (C=O) alquilo C1-6 o S(O)2Ra.Indole compounds of formula (1) which inhibit, regulate and / or modulate the transduction of tyrosine kinase signals, the compositions containing these compounds, and the methods of using them to treat diseases and conditions that depend on tyrosine are referred to kinase, such as angiogenesis, cancer, tumor development, arteriosclerosis, age-related macular degeneration, diabetic retinopathy, inflammatory diseases, and the like in mammals. Claim 1: An indole compound characterized in that it is of formula (1) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Z is formulas (2) or (3) or (4); W1 is S, O or N-R; V1 is N or C; W2 is N or C; V2 is S, O or N-R; a is 0 or 1; b is 0 or 1; m is 0, 1 or 2; s is 1 or 2; t is 1, 2 or 3; X = Y is C = N, N = C, or C = C; R is H or C1-6 alkyl; R1 and R5 are independently selected from: H, (C = O) aOb C1-10 alkyl, (C = O) aOb aryl, (C = O) aOb C2-10 alkenyl, (C = O) aOb C2-10 alkynyl , CO2H, halo, OH, Ob perfluoroalkyl C1-6, (C = O) to NR7R8, CN, (C = O) aOb C3-8 cycloalkyl, and (C = O) aOb heterocyclyl, said alkyl, aryl, alkenyl, alkynyl cycloalkyl and heterocyclyl is optionally substituted with one or more substituents selected from R6; R2 and R3 are independently selected from: H, (C = O) Oa C1-6 alkyl, (C = O) Oa aryl, C1-6 alkyl, SO2Ra, and aryl; R4 is selected from: (C = O) aOb C1-10 alkyl, (C = O) aOb aryl, (C = O) aOb C2-10 alkenyl, (C = O) aOb C2-10 alkynyl, CO2H, halo, OH, C1-6 perfluoralkyl Ob, (C = O) to NR7R8, CN, (C = O) a C3-8 cycloalkyl, and (C = O) aOb heterocyclyl, said alkyl, aryl, alkenyl, alkynyl, cycloalkyl and heterocyclyl is optionally substituted with one or more substituents selected from R6; R6 is (C = O) aOb C1-6 alkyl, (C = O) aOb aryl, C2-10 alkenyl, C2-10 alkynyl, (C = O) aOb heterocyclyl, CO2H, halo, CN, OH, Ob perfluoralkyl C1 -3, Oa (C = O) b NR7R8, oxo, CHO, (N = O) R7R8, or (C = O) aOb C3-8 cycloalkyl, said alkyl, aryl, alkenyl, alkynyl, heterocyclyl and cycloalkyl is optionally substituted with one or more substituents selected from R6a; R6a is selected from: C = O) rOs C1-10 alkyl, where rys are independently 0 or 1, Or perfluoralkyl C1-3, where r is 0 or 1, C0-6-S alkylene (O) mRa, where m is 0, 1 or 2, oxo, OH, halo, CN, C2-10 alkenyl, C2-10 alkynyl, C3-6 cycloalkyl, C0-6-aryl alkylene, C0-6-heterocyclyl alkylene, C0-6-N alkylene ( Rb) 2, C (O) Ra, C0-6-CO2 alkylene, C (O) H, and C0-6-CO2H alkylene, said alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl is optionally substituted with up to three substituents selected from Rb, OH, C1-6 alkoxy, halogen, CO2H, CN, O (C = O) C1-6 alkyl, oxo, and N (Rb) 2; R7 and R8 are independently selected from: H, (C = O) Ob C1-10 alkyl, (C = O) Ob C3-8 cycloalkyl, (C = O) Ob aryl, (C = O) Heterocyclyl ob, C1 alkyl -10, aryl, C2-10 alkenyl, C2-10 alkynyl, heterocyclyl, C3-8 cycloalkyl, SO2Ra, and (C = O) NRb 2, said alkyl, cycloalkyl, aryl, heterocyclyl, alkenyl and alkynyl are optionally substituted with one or more substituents selected from R6a, or R7 and R8 may be taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic heterocycle with 5-7 members in each ring and optionally containing in addition to nitrogen one or two additional heteroatoms selected from N, O and S, said monocyclic or bicyclic heterocycle being optionally substituted with one or more substituents selected from R6a; Ra is C1-6 alkyl, C3-6 cycloalkyl, aryl, or heterocyclyl; and Rb is H, C1-6 alkyl, aryl, heterocyclyl, C3-6 cycloalkyl, (C = O) OR C1-6 alkyl, (C = O) C1-6 alkyl or S (O) 2Ra.

ARP000105472A 1999-10-19 2000-10-18 INHIBITORS OF INHIBITORS OF THYROSINE KINASE, PHARMACEUTICAL COMPOSITION, PROCEDURE TO PREPARE IT, AND, USE OF THE COMPOUNDS IN THE PREPARATION OF MEDICINES AR035626A1 (en)

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